The
role of genetics in determining lifespan is complex and paradoxical. While the heritability of
lifespan is relatively minor, some genetic
variants significantly modify senescence in mammals and invertebrates, with both positive and
negative impact on the age-related disorders and
lifespans. In certain examples, the gene variants alter metabolic pathways, which could thereby
mediate interactions with nutrition and other
environmental factors that influence lifespan. Given the relatively low degree and variable
penetrance of genetic risk factors that appear to
affect survival and health at advanced ages, lifestyle and other environmental influences may
profoundly modify outcomes of aging.

Genes exert strong controls on the lifespan and
patterns of aging. Yet, we know little of how humans live five times longer than cats; cats, five
times longer than mice; mice, 25 times longer than fruit flies (1, 2), or why the onset of
Alzheimers Disease (AD) often differs by many years in identical twins. Equally obscure is the
role of genetics in the unprecedented increases of human life expectancy at advanced ages (1). To
approach these puzzles, we must understand how the potential lifespan of an individual is
determined by gene-environment interplay, which ultimately modulates the rates of molecular and
cellular involution during aging. Clearly, individual humans are subject to genetic risks for
age-related diseases, for example AD, cancer, diabetes, heart disease, and stroke. Other mammals
share subsets of these age-related diseases, but we do not know causes of mortality in flies or
worms (2). Since the incidence of diverse diseases accelerates exponentially with increasing age, it
is difficult to critically resolve whether general age-related changes, such as the loss of skin
elasticity and the slowing of reflexes, are mediated by the same mechanisms governing specific
age-related diseases.

The Heritability of Lifespans
is Small

A convergence of new and old data shows
that the heritability of lifespans accounts for <35% of its variance in short-lived invertebrates,
the nematode (3) and fruit fly (4), and in mammals, the mouse (5) and human (6, 7) (Table 1).
Two studies of human twins attribute most (>65%) of the variance to non-shared (individually
unique) environmental factors (6, 7). Twins reared apart share even less heritability of lifespan (7).
We do not yet appreciate the nature or penetrance of environmental influences acquired during
postnatal and prenatal phases, or even earlier in the life of the prezygotic oocyte (8).

Nonheritable variations in lifespan are also found in
laboratory populations of inbred lines of nematodes, fruit flies, and mice. Within each inbred line,
individuals show wide variations in lifespan which, expressed as the coefficient of variation,
approximate those of outbred populations (Table 1). Moreover, inbred worms and flies, but also
outbred human populations, display multiphasic changes in mortality rates during aging, such that
mortality rates initially accelerate exponentially with advancing age (Gompertzian mortality), but
then decelerate markedly among the last survivors (1, 2, 9). It remains possible that residual
genetic variations contribute to this demographic (actuarial) heterogeneity in inbred laboratory
animals (10).

Nonetheless, we do not depreciate the importance of
genetics to the evolution of lifespans which is exemplified by the efficacy of artificial selection for
longer or shorter lifespans in outbred fruit flies (2, 11, 12). Lifespan is considered by evolutionary
biologists to be a statistical outcome of selections for the reproductive schedule (1, 11-16).
Depending on the selection regime operating on a given population, the heritability of life spans, is
like other quantitative life history parameters that show heritabilities ranging from negligible to
nearly complete (11, 13). It is recognized from effects of diet restriction on lifespans of mice of
different genotypes (2) that gene-environment interactions can greatly modify lifespans. Thus,
transgenic approaches will be useful in identifying the dependency of genetic influences on
lifespan in different host backgrounds. It is also conceivable that transgenic experiments could
also evaluate if genes or alleles that influence lifespan within a given species may also modify the
lifespans of other species. However, it seems unlikely that a few genes determine the 25-fold
difference in lifespans between rodents and humans (2, 11, 15).

Gene Expression in
Aging

Mutations dramatically modify the lifespan of
fruit flies (11, 15, 17-19), and nematodes (15, 20-24) through mechanisms that may be shared by
common effects on metabolism and gene expression. In fruit flies, enhancer-trap systems (25)
detect transcriptional changes of exquisite specificity in their location and timing, for example the
decreased expression of wingless (wg) isrestricted to specific cells of the
antennae (23). However, the relatively greater expression of heat shock hsp70 in flight
muscles of old flies during stress responses is due to post-transcriptional age changes (17). In
rodent brain and other tissues, selective changes in gene activity are also observed (2), such as the
increased expression of the astrocyte cytoskeletal protein GFAP, which is due to increased
transcription (26).

Experimental manipulations of life span in flies and rodents also cause
corresponding changes in gene activity. During temperature-induced shifts in fruit fly life spans,
the age-schedule for decreased expression of wg and engrailed (en) in the adult
antenna (19) and for increased expression of hsp70 in muscle (17) is also shifted in
proportion to lifespan over a three-fold range (Fig. 1). Accelerated age changes in gene
expression occur in very short-lived mutants carrying drd, Hk1, or
Sh5(19), and in catalase-null flies (17). These cell-specific age changes
could not be detected in homogenates of whole flies, which are often used for biochemical studies
of aging. Taken together, the anatomic and temporal specificity of changes during aging, and their
scheduling in proportion to variations of lifespan in different situations, suggest the hypothesis
that changes in gene activity during aging in flies are physiologically coordinated through humoral
or neural factors. Although no data are available on how aging alters hormones or metabolites in
the hemolymph of fruit flies, in certain castes of honeybees, there are increases of juvenile
hormone that trigger senescence (2, 27). In view of the age changes in regulatory pathways
involving en(transcription factor) and wg (secreted
molecule mediating intercellular signaling), it will be of interest to examine expression of these
and related genes in flies of different lifespans that were selected for early and late reproduction
(11, 12).

The similar effects of very different mutations (drd,
Hk1, or Sh5) on accelerating age changes in gene
expression recalls the shared outcomes of defects in various genes that cause AD, all of which
increase production of the amyloid b -peptide (Ab ) and lead to similar neurodegenerative changes at later ages. The
potential influence of physiological factors in rat brain aging is shown by impact of food
restriction, which slows the age-related increases in GFAP transcription and other markers of glial
activation (26), while also increasing lifespan (2, 16, 18).

Gene expression is also altered during agingin bakers' yeast (Saccharomyces cerevisae), in which solitary mother cells
sustain a finite number of asexual replicative cycles that, through budding, yield a limited number
of progeny (28-31). Postreplicative yeast mother cells become enlarged, have changed optical
properties (granularity), and may lyse during the next hours to days. Mutants selected for stress
resistance (cold and nitrogen starvation) showed increased budding cycle lifespans on some
genetic backgrounds, for example the SIR4-42 allele of the UTH2/SIR4gene, which increased lifespan and stress resistance. The
SIR complex (Silent Information Regulator) transcriptionally silences genes at telomeres
and genes required for sexual mating (HML, HMR).
The mutant SIR4-42protein causes a
redistribution of SIR proteins from telomeres to the nucleolus, as also occurs in senescent
wild-type yeast cells (29, 30). Under- and over-expression of wild-type UT4correspondingly increases or decreases the number of budding
cycles. Mutation of the SGS1 gene, which encodes a DNA helicase with homology to the human
gene for Werner's Progeria, also causes premature aging with redistribution of Sir3 to the
nucleolus (30). The redistribution of telomeric silencing proteins is consistent with selective
transcription of previously silenced genes, HMRa1 (29)and certain subtelomeric
genes, such as URA3 (28). Other non-telomeric yeast genes also show altered expression
during aging, for example decreased expression of the "longevity determining genes"
LAG1 and RAS1 (28). The concentration of rRNA is lower in old yeast cells
(28), possibly consequent to the redistribution of SIR proteins to the nucleolus. In certain
mammalian brain neurons, the nucleolus shrinks at later ages through unknown mechanisms
(32).In the filamentous fungus Podospora anserina, a long-lived mutant was
mapped to a locus encoding grisea a copper-activated transcription factor implicated in
the mtDNA instability that occurs during senescence in this species (31).Taken together,
these findings suggest that selective changes of gene regulation have important roles in cell
phenotypes of aging, as is widely found in development. However, it remains to be learned how
many of the changes in gene activity during aging are secondary to other underlying causes, such
as oxidative damage to molecules in the extracellular matrix as observed in mammals (2, 15,
18).

Budding cycle senescence in single yeast cells differs from the
well-studied clonal (replicative) senescence of human diploid fibroblasts (33, 34)in which
telomeres shortenduring clonal senescence in vitro and in vivo (33).In yeast, telomeres do not shorten during budding cycle senescence (28), whereas induced
telomere shortening appears to increase lifespan (29). A broad similarity, however, is selectivity of
changes in transcription; so far, no examples of changes in homologous genes have come to light.
In view of the increased resistance of mammalian fibroblasts to apoptosis during potentially
prolonged postreplicative phases (33, 34), it will be of interest to learn details of cell involution
and eventual lysis in postreplicative yeast mother cells.

Towards a Genetics of
Longevity

Schächter, et al (35) proposed a three-part classification
of candidate loci for longevity: (i) genes with homologues that influence longevity in other
species; (ii) genes mediating cellular maintenance and repair; and (iii) genes associated with
susceptibility to major age-related diseases.

(i) A search is underway to find genes associated with longevity in
humans and other mammals, with a focus on the very elderly. In centenarians, the strongest
candidate is the e2 allele of the apolipoprotein E
(APOE) gene. The e4 allele, which promotes
vascular disease, was 50% less frequent than in younger controls, while the frequency of
e2, which is strongly associated with hyperlipidemia
when homozygous, was higher in centenarians (36). Nonetheless, occasional centenarians with
e4 /e4 are not demented (37). Italian
centenarians show 50% lower frequency of apoB with low tandem repeats (apoB-VNTR)
than in young controls, but this difference was not found in French or Finnish centenarians (38).
The multigene major histocompatibility system (HLA in humans, MHC in mice)
continues to spark interest as a source of longevity enhancing alleles. Mice carrying the
H-2dallele have longer lifespans, increased immune vigor, and fewer
lymphomas during aging (2, 5). Although centenarians show significant enrichment of up to
two-fold in certain alleles of the HLA -A, -C, and -DR series (39, 40), no finding
has yet been generalized across human populations.

Candidate longevity genes for humans are being found by
searches for single gene mutations that extend the lifespan of the nematode Caenorhabditis
elegans. Sixinduced mutations that extend life expectancy by 40 to 100% (20-23)
share increased resistance to stressors including temperature, free radicals, and UV light. The first
such mutation was age-1, which doubles maximum lifespan (20). Other nematode
mutations also associate extended adult lifespan with stress resistance. The greatest increases in
lifespan are associated with two genes that cause constitutive formation of the dauer larval stage (Table 1): age-l, identified with a
phosphatidyl-inositol-3-OH kinase (22), and daf-2, with an insulin receptor-like gene (23).
daf-2 activation by the dauer pheromone is hypothesized to be mediated by PIP-3
(23). This mechanism would be consistent with genetic evidence that daf-2 and
age-1 participate in an epistatic pathway (21) and the greater lipid accumulation of
daf-2 mutants (23). The regulation of nematode lifespan by insulin-like signaling is
consistent with the extension of lifespan in rodents by food restriction (2, 18). Another set of
long-lived mutants are those involving the clock gene (clk), which have slowed
development, lengthened cell cycles, and modified adult behavior (24). clk-l encodes a
short protein, an 82 amino acid tandem repeat which is highly conserved in eukaryotes; its yeast
homolog CAT5/COQ7 indirectly regulates the transcription of genes that modulate
energy metabolism to permit growth on nonfermentable carbon sources. The longest lived C.
elegans are daf-2/clk-1 double mutants with a five-fold increase in lifespan (24). The
increase of total life span by the dauer mutations daf-2 and daf-23 represents a
two-fold increase in the adult phase in addition to the extended development.

(ii) A longevity locus for cellular maintenance is indicated by
loss-of-function in the recently identified gene for the Werner's Syndrome, a rare autosomal
recessive adult-onset progeroid with early manifestations of aging, such as hair loss, skin atrophy,
premature heart disease, and various tumors. The Werner gene resembles the DNA (RecQ)
helicases (41). Loss-of-function mutations in this gene lead to impaired DNA replication or DNA
repair, resulting in the accumulation of various somatic DNA mutations and rapid decrease in
telomere length (15). In contrast to the fruit fly mutations that accelerate multiple changes in gene
expression, the Werner progeria mutations do not uniformly accelerate aging, e.g., there is no
evidence for cognitive decline or AD. Nonetheless, because mutation of a yeast homologue also
induced a progeroid phenotype (30), it is possible that that helicase functions could mediate a
wider range of cellular aging changes than previously thought. A common polymorphism in the
Werner progeria gene was recently associated with 2.7-fold higher risks of heart attacks (41), but
the cellular mechanisms involved are not defined.

(iii) The third category includes genes involved in age-related
neurodegenerative, cardiovascular, cancer, and immunological disorders. AD is an increasingly
common neurological disorder of the elderly, which accounts for 70% of all cases of late-onset
dementia (after 60 years of age) and currently causes greater than 100,000 deaths per year in the
US (42). Because the incidence of AD doubles every five years after 60 years of age (42), the
incidence of AD is expected to increase further as more survive to advanced ages. Characteristic
neuropathological features of AD include neurofibrillary tangles (NFT) and extracellular deposits
of Ab in senile plaques and cerebral blood vessels. NFT and
Ab also accumulated to a lesser extent in individuals who
reach advanced ages without clinical dementia (42). Although everyone might develop AD if they
lived long enough, environmental risk factors most likely interact with genetic risk factors to
determine age of onset. This argument can be extended to cancers, because carcinogenic
determinants that vary with advancing age (greater than 30 years of age) appear to be distinct
from those that are environmentally determined (43). The former may involve impaired DNA
surveillance or activation of quiescent cells with damaged DNA. Meanwhile, impaired cell death
(apoptosis), in combination with increased cellular proliferation, may underlie age-dependent
decreases in the suppression of tumor formation due to an altered tissue microenvironment (44).
The accumulation of replicatively senescent fibroblasts in vivo during aging could alter the
cellular microenvironment by the increased secretion of proteases and other matrix-degrading
enzymes (33).

The Genetics of Alzheimer's Disease and Cell
Death

In contrast to the findings on lifespans, genetic
effects are found in late-onset cognitive declines. In twins, the concordance with diagnosed AD
(up to death) was two- to three-fold greater for MZ than DZ pairs (45). However, the onset of
AD varied widely, with only 50% of concordant MZ or DZ pairs becoming demented within five
years of the first (within-pair differences in onset ranged from 0 to 16 years). The estimates of AD
that are attributed to known and undefined genetic risk factors show decreases at later ages. This
trend parallels vascular disease risk factors in twins and diminishing genetic influences on blood
lipids at later ages (46).

Although most AD occurs in populations older than 60 years,
approximately 5% arises before 60 years of age (47), when it is frequently clustered in families
[early onset Familial AD (FAD)]; this is autosomal dominant and virtually 100% penetrant (42).
These genetically heterogeneous conditions involve defects in at least three different genes and
lead to indistinguishable neuropathology. The major component of brain amyloid in AD brains is a
4-kD peptide (Ab ) derived during the processing of the
amyloid b -protein precursor (APP) (42). Many missense
FAD mutations in the APP gene cluster around the Ab
domain and increase the production of Ab . Transgenic mice
with APP mutations accumulate Ab in the brain, but without
neuronal loss or NFT (42, 48). This result suggests that Ab
deposits may be necessary, but are not sufficient to yield AD-like neuropathology, at least in the
mouse brain. Ongoing studies may show whether other AD components such as human forms of
the tau protein, a main component of NFT, or of human forms of genes expressed in glia
are required to induce AD in mice. In transgenic mice over expressing wild-type APP, early death
and brain abnormalities occurred in the absence of Ab
deposits. Since early death also occurs in 20% of nontransgenic mice of this strain (FVB/N), APP
overexpression may accelerate a natural, age-related brain disorder (49).

Mutations in APP and in the presenilins, PS-1 and PS-2, account
for 50% of the occurrence of FAD (42). The vast majority of FAD mutations occur in PS-1, each
being atypically restricted to single family (42). Despite this genetic diversity, AD may nonetheless
deve1op from a broadly shared pathogenic process. Most FAD mutations in APP, PS-1, and PS-2
increase the secretion of Ab , by favoring the production of
'long' Ab , a form of the peptide with 42 rather than 40
residues, which is more prone to aggregations and to forming Ab deposits in the brain (42). These data argue for a central role of
Ab 42 in amyloid deposits of AD brains. Moreover, the
APOE-e4 allele is associated with increased
Ab load in AD brains (42, 50). The e4 allele is associated with late-onset AD and stroke due to
Ab deposits in cerebral blood vessels (51). The risk for AD
conferred by e4 is greatest for onset between 61 and
70 years of age (47). Meanwhile, the e2 allele is
associated with a decreased risk for AD, which is consistent with its association with longevity
(36).

Although functions of the presenilins are unknown, they have
50% similarity to the C.elegans protein SEL-12 which is a facilitator of the
LIN-12 Notch receptor. Moreover, the death of PS1-null mouse embryos from defects in somite
segmentation indicates that presenilins have key roles of the presenilins in axial skeleton
development (52). Presenilins are also substrates for a caspase-3 family protease during induced
apoptosis. Moreover, the PS2-N141I FAD mutation confers increased susceptibility to apoptosis
and increased cleavage of the PS-2 protein by caspase-3 (53). Caspase 3-generated presenilin
fragments could, in turn, also make cells more vulnerable to apoptosis. Apoptosis in aging can
either be beneficial by eliminating dysfunctional cells so that they can be replaced by proliferation
(homeostasis), or detrimental by eliminating irreplaceable cells such as neurons, leading to
neurodegeneration. For example, in aging rodents, D2-dopamine receptor-containing neurons are
lost through apoptosis, whereas apoptosis decreases the accumulation of nonfunctional T-cells
during food restriction (54).

Apoptotic death of neurons during AD (55, 56) may result from
impaired energy metabolism and the enhanced generation of 4-hydroxynonenal (HNE)(56), a key
mediator of neuronal apoptosis induced by oxidative stress. Alternatively, neuronal death in AD
could be due to enhanced caspase-mediated cleavage of the presenilins in association with
increased vulnerability to apoptosis (53) or to altered interactions of presenilins with concatenin
proteins (57). The concatenins also interact with edematous polyposis coli (APC) tumor
suppressor, the inactivation of which can lead to increased proliferation or inhibition of apoptosis
owing to transcriptional activation mediated by b -catenin
(58). Mutations in either APC or b -catenin occur in
one-third of melanomas (59). Thus, b -catenin may become
oncogenic when mutated or upregulated by inactivation of APC. Since b -catenin can also interact with the presenilins, endoproteolysis of
PS-1 or PS-2 may serve to regulate proliferative vs. apoptotic signals mediated by catenins. The
involvement of the catenins in the Wingless signaling pathway of fruit flies, which is mutually
inhibitory with Notch (60), may explain how a nematode presenilin homolog, SEL-12, facilitates
the LIN-12 Notch receptor.

Alternate Life
Histories

Genetic variants in the invertebrate models
described above show that altered scheduling of aging can arise from induced mutations, with
great shortening or lengthening of lifespans. Moreover, environmental factors may determine
alternate life histories within the same population. An instructive example is the l0-fold difference
in lifespans of female worker bees (Apis mellifica),which have rapid senescence
and lifespans of months, whereas queens of the same genotype show much slower senescence
during lifespans of many years of active egg production. These alternate life histories in females
are determined by exposure of larvae to nutrients and juvenile hormone.

Brown trout (Salmo trutta) also have several coexisting
life histories, with the giant ferox trout living more than five times longer than smaller sized trout
(2, 61). At a critical body size, some adult brown trout switch from plankton feeding to piscivory,
which allows faster growth and, contrary to predictions from food-restriction theory (2, 18), a
much longer lifespan (61). A possible genetic basis is the much higher prevalence of a Lactic
DeHydrogenase allele (LDH-5) in ferox than in the small, short-lived brown trout in the
same local population. In the killifish (Fundulus heroclitus),geographic
subpopulations differ in LDH alleles and isozyme activities that were shown experimentally to
alter rates of development (62).

When these examples are considered together with the C.
elegans mutations that modify metabolism and lifespan, it seems plausible that metabolic
regulation may be a general feature of life history variants. These examples are also consistent
with the evolutionary theory of life histories, in which selection for the duration and frequency of
reproduction indirectly modifies the potential lifespan (11, 13-15). The extensive plasticity in adult
lifespans is also represented in the recent major increases of human lifespan, although it is not
obvious how this increase could have resulted from natural selection.

Conclusions

During recent
centuries, technological advances that allow a higher quality of life and general health have
revealed an untapped potential of the human genome to support major increases in life expectancy
at all ages (1). Nonetheless, the explosive increase of cancer, vascular disease, and AD at later
ages were not widely experienced in historical human populations, so that there was little
selection against these diseases at their present age of occurrence (2, 11, 14, 15). Ironically,
genetic tools that were developed in the various genome projects now allow easy identification of
genetic risk factors such as those for conditions that may comprise health in later years. One
might consider that, if the human life expectancy should approach the present record of 122 years,
some existing gene polymorphisms which may be "lying in wait" could rise up to challenge the
quest for health at advanced years. The growing inventory of genetic and environmental factors
affecting the lifespan, along with an understanding of gene-to-gene and gene-environment
interactions, should arm us well for the continuing battle with morbidity. Genetic studies of
age-related human diseases and longevity mutants of animal models have identified many risk
factors that affect metabolism and resistance to stress. Future studies of animal and cell models of
aging should identify many paths, some of them convergent, by which environmental factors
modify genetic risk factors in aging. The relatively minor heritability of human lifespan at
advanced ages and the variable penetrance of genetic risk factors implies that choice of life style
profoundly influences the outcomes of aging (63).

Table 1:

Heritability and Variance
Characteristics of Lifespans in Selected Vertebrates and Invertebrates.

Species

Heritability of Lifespan*

Coefficient of Variation of Lifespan §

Lifespan (Mean)

Nematode (3)

15 days (25°C)

within line

0 (self-fertilizing)

34%

between lines

0.34

19% (16-24%)

Flies

Fruit fly, inbred lines (4)

40 days (25°C)

within line

[<0.01]

between lines

0.06-0.09

11%

Medfly, outbred (9)

not determined

45%

21 days (25°C)

Mouse, inbred lines (5)

27 months

within line

[<0.01]

24% (18-71%)

between lines

0.29

16%

Human twins (6, 7)

72 years

0.23-0.33

MZ, 19%; DZ, 25%

* A linear model partitioned the heritability of lifespans into additive,
dominant, and epistatic components (3-7). For animal models, values are "narrow sense
heritability" that represents the additive component (64). For human twin monozygous (MZ) and
dizygous (DZ) pairs from Denmark (6) and Sweden (7), ennvironmental terms were included in
the model (64); the values show the range of heritability in both studies. Danish twins (6) showed
the best fit with a model of dominant heritability and non-shared environment.

§ The coefficient of variation for lifespan is the standard
deviation of lifespan in the population as a percent of the mean lifespan (65). Variations of
lifespan within inbred lines could represent the microenvironment (66), but also residual genetic
variations (10, 64).

8. In humans, the unfertilized egg typically exists for twenty or more
years as a cell in the mother's ovary, which because of its origin before her birth, could carry
influences from the matrilineal grandmother (C. E. Finch and J. C. Loehlin, Behav. Genetics,
in press). Prefertilization influences in mammals are less likely for sperm, which are generally
short-lived. However, social insect queens store sperm for many years.

9. J. R. Carey, et al., Science, 258,457
(1992).

10. A caveat is that variations in lifespan observed in certain inbreeding
situations could represent residual genetic variance. Brother-sister inbreeding can achieve
<0.001 residual genetic variance, but may never reach "0" because of point mutations and
chromosomal rearrangements, including unstable mobile genetic elements (P-elements, flies;
retroviruses, mice) and expansion-contraction of trinucleotide repeats. Self-fertilizing nematodes
more readily approach isogenicity (3), although spontaneous mutations could still lead to
genetically distinct subpopulations that would be hard to detect. Mitochondrial DNA replication is
more error-prone and could also contribute variations to chromosomally isogenic strains.

25. Enhancer-trap systems are random inserts used to identify genes that
change in transcriptional activity. Flies are engineered to contain a single insertion of a P-type
transposable element with a weak promoter and a reporter gene whose product generates a
histochemically detected product. When the nearby gene becomes active, the trapped reporter
may be detected and localized to particular cells. Insertional genetic techniques, such as required
for enhancer-trapping and to increase gene copy number for testing hypotheses about aging (16,
22), may induce position effects that may haphazardly modify lifespan and details of aging [M.
Kaiser, M. Gasser, R. Ackerman, and S. C. Stearns, Heredity, 78, 1
(1997)].

63. These projects were supported by grants to C.E.F. from the N.I.A.
and to R.E.T. from the N.I.A., N.I.N.D.S., and the Metropolitan Life Foundation. T. Johnson, G.
McClearn, R. Miller, M. Tater, and J. Tower gave helpful comments.

64. The value for nematodes is the average of calculations from three
different experimental paradigms, each replicated (3).

66. Variations in lifespans must also depend on local conditions. For
example, total lifespans of C. elegans can be more than three-fold longer if a lack of
nutrients during development triggers the dauer larval stage; the dauer may last
70 days without altering the adult phase, once food becomes sufficient (2, 20-23). Social and
reproductive interactions can also increase mortality risk in flies and mice. The present sampling
of populations under protected conditions nonetheless have similar variations in lifespan that give
a sense of baseline variations. Also, see Notes 10 and 25.

Figure 1:

Expression of the wg in Fruit
Flies During Aging Changes in Proportion to the Lifespan.

A. The green color* shows the reporter signal from an enhancer-trap line in control flies
(lifespan, 40 days) and in the short-lived mutant drd (lifespan, 6 days).

B. Expression of wg decreases gradually during aging in control antennae and more
rapidly in drd.